This Program Project, comprised of 3 Projects and 2 Cores, explores the signaling mechanisms of activins, BMPs, inhibins and their receptors and binding proteins as they modulate the reproductive and other systems. Project I (Vale) recently identified the proteoglycan, betaglycan, as a putative inhibin co-receptor. This project will investigate the mechanisms by which inhibin interacts with betaglycan and activin receptors to antagonize activin and selected BMPs. Furthermore, the physiologic importance of betaglycan will be tested by immunoneutralization or disruption of its expression in vitro and in vivo. Project I will characterize betaglycan variants and seek additional inhibin co-receptors. Project II (Choe) has solved the X-ray crystallographic structure of the type II receptor extracellular ligand-binding domain (ActRII- ECD) both alone and in a complex with the activin paralog, BMP-7. The structure of BMP-7 with its inhibitory binding protein, noggin, has also been solved. Project II proposes to elucidate additional structures, including triple complexes, comprising activins or BMPs bound to their type II and/or type I ECDs as well as inhibin bound to ActRII and/or betaglycan ECDs. As additional structural information is provided by Project II it will be used by Projects I and Ill to further characterize the structure/function relationships between inhibins, activins, BMPs and their receptors. Project III (Fischer) uses computer modeling and X-ray structure data, obtained in close collaboration with Project II, to design mutant ligands and receptors to be tested for their effects on ligand:receptor binding interactions. Activin mutants will be used to test hypotheses regarding interactions with type II and type I activin receptors and follistatin. Core A (Vale) provides administrative and computer support, evaluation of progress and coordinates interactions with the Advisory Panel and NICHD staff. Core B (Fischer, Rivier, Choe & Vale) provides technical support and reagents, including antisera towards activin/inhibin signaling molecules, and conducts RIAs for pituitary and gonadal hormones. This Core provides synthetic peptides and expresses and purifies recombinant activin and inhibin and various other proteins including receptor components. The Core characterizes native and recombinant proteins by automated sequencing and mass spectrometry. This Program brings together a diversity of approaches to address fundamental issues surrounding activin and BMP signaling and their counter-regulation by inhibin and binding proteins. Because of the physiologic and pathophysiologic significance of activins, BMPs, and inhibins, these studies should serve to illuminate potential means for the control of human fertility and management of medical disorders.